Peroxisome proliferator-activated receptor gamma belongs to the nuclear receptor superfamily and is activated by the antidiabetic drugs rosiglitazone and pioglitazone. Ligand-independent constitutive activity of peroxisome proliferator-activated receptor gamma is also demonstrated. X-ray crystallographic structures show that the active or inactive conformations of the receptor are determined by the position of helix 12 in the C-terminal end. In this study, molecular dynamics simulations were used to gain molecular insight into the activation process and the structural stability of inactive and active peroxisome proliferator-activated receptor gamma receptor structure. The simulations showed: (i) during molecular dynamics simulations without agonist at the active site, the receptor structure with helix 12 in a position corresponding to activated receptor structure was structurally more stable than with helix 12 in a position corresponding to inactive receptor structure, which may contribute to the constitutive activity of the receptor; (ii) docosahexenoic acid stabilized the active receptor conformation more efficiently than the glitazones; (iii) docosahexenoic acid, but not glitazones, induced structural changes into the inactive receptor structure such that helix 12 was shifted into a position more similar to that of an active receptor structure, which indicate that docosahexenoic acid is a more effective peroxisome proliferator-activated receptor gamma agonist than the glitazones.